Phosphodiesterase 2 as a Therapeutic Target for Heart Failure: Is Upregulation an Option?

Abstract

Heart failure (HF) is a chronic progressive cardiac disease with high morbidity and mortality.1 A key pathophysiological feature of HF is chronic overexcitation of the sympathetic nervous system and release of catecholamines.2 The subsequent activation of cardiac β-adrenoceptors (β-ARs) results in molecular and structural changes that lead to cardiac hypertrophy, myocardial fibrosis, or electromechanical dysfunction. This cascade of cellular events creates a setting for lethal cardiac arrhythmias and increases the prognostic risks for mortality and detrimental cardiovascular outcome.3 Accordingly, pharmacological intervention with β-blockers remains a mainstay practice in clinical management of HF.4 Nevertheless, chronic β-blocker therapy is known to be accompanied by adverse side effects that include bradycardia, heart block, bronchospasm, fatigue, muscle cramps, and sleep disturbances.5 Furthermore, not all patients experiencing HF benefit from β-blocker treatments or tolerate the doses necessary to achieve disease improvement.6 These disadvantages prompted the quest for alternative medication against HF with therapeutic targets other than β-ARs. Article, see p 120 There are 3 subtypes of β-ARs: β1-, β2-, and β3-AR. Both β1-AR and β2-AR can be found in healthy cardiac cells, and the expression of β3-AR is considerably low in the unstressed heart.7,8 In the failing heart, β1-AR and β3-AR expression are, respectively, decreased9 and increased.8 However, changes in β2-AR levels are somewhat controversial, varying from increase10 to decrease.11 After catecholamine stimulation, both β1-AR and β2-AR couple to adenylyl cyclase stimulatory G protein, Gs, leading to cAMP accumulation within the myocyte and activation of protein kinase A (PKA).12 In contrast, β3-AR activation increases the activity of protein kinase G via cGMP-dependent signaling.13 The cAMP/PKA signaling …